This invention relates to a process for the preparation of alcohols by the addition of organometallic reagents to ketones. More particularly, this invention relates to the reaction of 1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives with organometallic compounds derived from alpha-haloalkylpyrimidines to form tertiary alcohols.
The reaction of organometallic compounds derived from alkyl halides with aldehydes and ketones to form secondary and tertiary alcohols, respectively, is well established in the field of organic chemistry. Many different metals and metal derivatives have been reported as being useful in this type of reaction, including lithium, magnesium, aluminium, tin and zinc, together with salts thereof. For example, A. R. Gangloff et al, J. Org. Chem., 57, 4797-4799 (1992) discloses that 2-(bromomethyl)-4-carbethoxy-1,3-oxazole reacts with zinc dust to form an organozinc derivative which undergoes nucleophilic addition to aldehydes and ketones. Also, Chollet et al, Synth. Comm., 19 (11 and 12), 2167-2173 (1989) reports the reaction of organozinc derivatives of bromoesters with aldehydes and ketones.
Certain compounds prepared according to the present process are disclosed in European Patent Application Publication numbers 0357241 and 0440372.
It has now been surprisingly found that certain 1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives may be reacted with organometallic compounds derived from certain alpha-haloalkylpyrimidine derivatives to form tertiary alcohols in good to excellent yields and with high stereoselectivity using reaction conditions that are particularly suitable for the bulk synthesis of the product.
This finding has been found to be particularly useful for the synthesis of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-1,2,4-triazol-1-yl)butan-2-ol, a key intermediate for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, a compound having antifungal activity. The syntheses of both of these compounds have been described in European Patent Application Publication number 0440372. In this Application, (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol is prepared by the chromatographic separation of the two pairs of enantiomers obtained from the addition of an organolithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at from xe2x88x9270 to xe2x88x9250xc2x0 C. The best stereoselectivity that has been obtained in this addition is a 1.1:1 molar ratio in favour of the 2R,3S/2S,3R enantiomeric pair with the total isolated yield of all four stereoisomers being only about 50%, the low yield being thought to be due to a competing enolisation reaction. These factors, coupled with the need to operate the addition reaction at very low temperatures and under very dilute conditions, together with the difficulty in separating approximately equimolar amounts of the two pairs of enantiomers at the end of the reaction with the 2R,3R/2S,3S enantiomeric pair being unwanted, mean that the process is extremely unsuitable for the economic preparation of the required 2R,3S/2S,3R intermediate on a large scale.
In contrast, for example, it has now been found that a 9:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and a 65% isolated total yield of all the enantiomers (as the hydrochloride salts) can be obtained under the reaction conditions according to the present invention that are highly suitable for large scale synthesis of the product.
However, higher isolated yields have been obtained and higher molar ratios (both in situ and in respect of isolated product) have been determined by varying the reaction conditions in accordance with the present invention.
Similar results have been obtained with a range of alpha-haloalkyl-pyrimidine substrates.
Considerable economic advantages result from the yields and stereospecificity achieved.
The present invention provides a process for the preparation of a compound of the formula: 
or an acid addition or base salt thereof, wherein
R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl;
R1 is C1-C6 alkyl; and
xe2x80x9cHetxe2x80x9d is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, oxo, benzyl and benzyloxy,
comprising reaction of a compound of the formula: 
wherein R is as previously defined for a compound of the formula (I), with a compound of the formula: 
wherein R1 and xe2x80x9cHetxe2x80x9d are as previously defined for a compound of the formula (I) and X is chloro, bromo or iodo, in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent: said process being optionally followed by formation of an acid addition or base salt of the product.
Optionally, lead can also be present in the reaction, either as the metal per se or in the form of a suitable salt, e.g. a lead (II) halide. It can be added separately or be inherently present in the zinc used.
In the above definitions, alkyl and alkoxy groups containing three or more carbon atoms may be straight- or branched-chain and xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
Preferably, R is phenyl optionally substituted by 1 to 3 halo substituents.
More preferably, R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro.
Yet more preferably, R is phenyl substituted by 1 or 2 fluoro substituents.
Most preferably, R is 2,4-difluorophenyl.
Preferably, R1 is C1-C4 alkyl.
More preferably, R1 is methyl or ethyl.
Most preferably, R1 is methyl.
Preferably, xe2x80x9cHetxe2x80x9d is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from halo, oxo and benzyl.
More preferably, xe2x80x9cHetxe2x80x9d is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from fluoro, chloro, oxo and benzyl.
Yet more preferably, xe2x80x9cHetxe2x80x9d is pyrimidinyl substituted by 1 to 3 substituents each independently selected from fluoro and chloro.
Preferred examples of xe2x80x9cHetxe2x80x9d include pyrimidin-4-yl, 4-chloro-5-fluoropyrimidin-6-yl, 5-fluoropyrimidin-4-yl, 2-chloro-5-fluoropyrimidin-6-yl, 2,4-dichloro-5-fluoropyrimidin-6-yl, 4-chloropyrimidin-6-yl and 1-benzyl-5-fluoropyrimidin-6-on-4-yl.
Most preferably, xe2x80x9cHetxe2x80x9d is 4-chloro-5-fluoropyrimidin-6-yl.
Preferably, X is bromo or iodo.
Most preferably, X is bromo.
The compound of the formula (II) may be an enolisable ketone. Most preferably, the compound of formula (II) is 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone.
Preferably the compound of the formula (III) is selected from 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine, 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine, 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine, 4-(1-bromoethyl)pyrimidine, 4-(1-bromoethyl)-6-chloropyrimidine, 4-(1-bromoethyl)-5-fluoropyrimidine and 1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one.
Most preferably, the compound of the formula (III) is 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine.
The reaction is carried out in the presence of a suitable aprotic organic solvent such as tetrahydrofuran, toluene, 1,2-dimethoxyethane or methylene chloride, or a mixture of two or more thereof. It is highly desirable to dry the solvent before use to remove substantially all traces of water. Drying can be achieved using a desiccant such as magnesium sulphate, sodium sulphate or molecular sieves, by distillation from a metal such as lithium, sodium or potassium or by azeotropic distillation.
The preferred solvent for the reaction is tetrahydrofuran.
It is also preferable to carry out the reaction under a dry, inert atmosphere such as by using dry nitrogen or argon gas.
The zinc used in the reaction may be zinc powder derived from a commercial source or it may be freshly generated in situ by the reduction of a zinc halide (e.g. zinc chloride) using lithium, sodium or potassium (see, e.g., R. D. Rieke, Acc. Chem. Res., 10, 301 (1977)). The zinc powder may be activated prior to use by stirring a slurry of the powder for several hours in a suitable solvent, e.g. tetrahydrofuran.
Optionally, the reaction is carried out in the additional presence of lead.
The zinc powder obtained commercially may contain small amounts of lead as an impurity and the lead content can be up to about 2000 parts per million (0.20 weight %) depending on the source. However, it is generally preferred to increase the lead content by adding lead in the form of lead powder to the reaction mixture. Lead powder is commercially available.
Preferably, when used, the amount of lead present in the reaction is 2000 ppm (0.2 wt %) or more relative to the amount of zinc present. More preferably, the amount of lead present is from 2000 to 100,000 ppm (0.2 to 10 weight %). Most preferably, the amount of lead present is about 50,000 ppm (5 wt %).
Iodine is generally used in its commercially available crystalline form. It is suspected that its role in the reaction is in the in situ generation of zinc iodide, possibly, when lead is also present, in conjunction with lead (II) iodide as well, both of which may function as catalysts.
Iodine, when used, may be introduced into the reaction vessel before, during or after the compounds of the formulae (II) and (III) have been added. Alternatively, it can be added in at least two stages, for example, one portion can be added to the reaction vessel before, and the second portion can be added when, the compounds of the formulae (II) and (III) are added.
Suitable Lewis acids for use in the reaction include zinc chloride, zinc bromide, zinc iodide, titanium (IV) isopropoxide, chlorotitanium triisopropoxide, titanium tetrachloride, trimethyl borate, boron trifluoride (etherate), iron (III) chloride and diethylaluminium chloride.
Preferred Lewis acids are zinc bromide, zinc iodide and, particularly, zinc chloride.
Iodine is preferably used rather than separately adding a Lewis acid.
Optionally, both iodine and a Lewis acid may be used in the above process.
The reaction may be carried out at from xe2x88x9215xc2x0 C. to the reflux temperature of the mixture. Preferably, it is carried out at from xe2x88x9210 to +30xc2x0 C. and most preferably from xe2x88x9210xc2x0 C. to +15xc2x0 C.
The reaction almost certainly proceeds via formation of an organozinc species derived from the in situ reaction of zinc with a compound of the formula (III) that is used as a starting material.
The reaction may be carried out by the following general procedure. is Iodine and/or a suitable Lewis acid are/is added to a stirred mixture of zinc, optionally lead, and a suitable aprotic organic solvent. The mixture is cooled and a solution of a compound of the formula (II), a compound of the formula (III) and, optionally, further iodine in a suitable aprotic organic solvent is added, cooling the mixture during the addition. The mixture is stirred for a further short period before being warmed to room temperature. The reaction is quenched by adding glacial acetic acid followed by water and conventional work-up techniques can then be used in order to isolate the required product.
The process is optionally followed by formation of an acid addition or a base salt of the product. Formation of an acid addition salt is preferred and suitable salts include the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, methanesulphonate, camphorsulphonate, R-(xe2x88x92)-10-camphorsulphonate, (+)-3-bromo-10-camphorsulphonate, (xe2x88x92)-3-bromo-8-camphorsulphonate, phosphate, para-toluenesulphonate and benzenesulphonate salts. The hydrochloride salt is particularly preferred.
A compound of the formula (I) produced by the process of the invention contains two or more asymmetric carbon atoms and therefore exists in four or more stereoisomeric forms.
The reaction generally proceeds with high stereoselectivity in favour of the (2R,3S/2S,3R) enantiomeric pair of a compound of the formula (I), i.e. 
where the asterixes (*) indicate the subject asymmetric carbon atoms.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. Resolution of enantiomers of a compound of the formula (I) may be achieved by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid, e.g. R-(xe2x88x92)-10-camphorsulphonic acid.
The process is preferably used to prepare 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol from the starting materials 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone and 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. High stereoselectivity can be achieved in the reaction with, for example, a 9:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair being obtained if the reaction conditions are carefully controlled. In addition, for example, a 65% isolated total yield (as the hydrochloride salts) of all the enantiomers has been obtained.
The reaction product, which contains a far higher proportion of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride, can be reduced to provide (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol which can be resolved to provide (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol by the method described in European Patent Application Publication number 0440372.
In a further aspect, the present invention provides a process for the preparation of a compound of the formula: 
or an acid addition salt thereof, wherein R and R1 are as previously defined for a compound of the formula (I) and R2 is H or fluoro, which comprises the steps of:
(a) reaction of a compound of the formula: 
wherein R is as defined for a compound of the formula (IV), with a compound of the formula: 
wherein X is chloro, bromo or iodo, R1 and R2 are as previously defined for a compound of the formula (IV) and either R3 and R4 are each independently selected from chloro and bromo or one of R3 and R4 is chloro or bromo and the other is H, in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent, to provide a compound of the formula: 
wherein R, R1, R2, R3 and R4 are as previously defined for this step (a);
(b) optionally converting the compound of the formula (IA) to an acid addition salt thereof;
(c) reduction of the compound of the formula (IA) or an acid addition salt thereof to provide the compound of the formula (IV); and
(d) optionally converting the compound of the formula (IV) to an acid addition salt thereof.
The reactions conditions, including the preferred conditions, used for step (a) are as previously described for the preparation of a compound of the formula (I). Again, optionally, lead can also be present in step (a).
The reduction in step (c) can be carried out under any conditions suitable for the replacement of one or more of the R3/R4 groups where R3/R4 is chloro or bromo by hydrogen.
The reduction may be carried out under conventional hydrogenation conditions using a suitable catalyst, e.g. palladium-on-charcoal, optionally in the presence of a suitable base, e.g. sodium acetate, and in a suitable solvent, e.g. ethanol, under a hydrogen atmosphere.
Preferably, the reduction is carried out under transfer hydrogenation conditions using a suitable catalyst, e.g. palladium or rhodium, a suitable hydrogen donor, e.g. ammonium or potassium formate, and in a suitable solvent, e.g. methanol. The reaction is preferably carried out at the reflux temperature of the solvent and under a nitrogen atmosphere.
Examples of acid additions salts in step (b) include the hydrochloride, nitrate, methanesulphonate, p-toluenesulphonate, camphorsulphonate, R-(xe2x88x92)-10-camphorsulphonate, (+)-3-bromo-10-camphorsulphonate and (xe2x88x92)-3-bromo-8-camphorsulphonate salts. Preferred acid addition salts in step (b) are the hydrochloride, methanesulphonate and p-toluenesulphonate salts.
A preferred acid addition salt in step (d) is the R-(xe2x88x92)-10-camphorsulphonate which may be used to resolve enantiomers of the compound of the formula (IV). A S-(+)-10-camphorsulphonate salt may also be generated and used for this purpose.
In this process for the preparation of a compound of the formula (IV):
(i) Preferably, R is phenyl optionally substituted by 1 to 3 halo substituents.
More preferably, R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro.
Yet more preferably, R is phenyl substituted by 1 or 2 fluoro substituents.
Most preferably, R is 2,4-difluorophenyl.
(ii) Preferably, R1 is C1-C4 alkyl.
More preferably, R1 is methyl or ethyl.
Most preferably, R1 is methyl.
(iii) Preferably, X is bromo or iodo.
Most preferably, X is bromo.
(iv) Preferably, R2 is fluoro.
(v) Preferably, R3 is chloro and R4 is H, R3 is H and R4 is chloro or R3 and R4 are both chloro.
(vi) Preferred compounds of the formula (IIIA) include:
6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine,
6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine,
6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine and
4-(1-bromoethyl)-6-chloropyrimidine.
(vii) Preferred compounds of the formula (IA) include:
3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,
3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,
3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and
3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,
and the acid addition salts thereof, particularly the hydrochloride, methanesulphonate and p-toluenesulphonate salts.
(viii) Preferred compounds of the formula (IV) include:
2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and
2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,
and the acid addition salts thereof, particularly the S-(+)- or R-(xe2x88x92)-10-camphorsulphonate salts.
The preparations of the starting materials used in the process of the present invention are conventional and appropriate reagents and reaction conditions for their preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Preparations hereto.
The present invention also provides the following novel compounds:
(i) (2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;
(ii) an acid addition salt of (2R,3S/2S,3R)- or (2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and preferably a hydrochloride, nitrate, methanesulphonate, p-toluenesulphonate, camphorsulphonate, R-(xe2x88x92)-10-camphorsulphonate, (+)-3-bromo-10-camphorsulphonate or (xe2x88x92)-3-bromo-8-camphorsulphonate salt;
(iii) 3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition salt of any thereof;
(iv) 3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition salt of any thereof;
(v) 3-(1-benzyl-5-fluoropyrimidin-6-on-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition salt of any thereof;
(vi) 3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition salt of any thereof;
(vii) 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine;
(viii) 4-(1-bromoethyl)-6-chloropyrimidine;
(ix) 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine;
(x) 1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one;
(xi) 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine;
(xii) 4-(1-bromoethyl)-5-fluoropyrimidine;
(xiii) 2-chloro-6-ethyl-5-fluoro4-hydroxypyrimidine, ammonium salt.